The following projects have been or are currently being conducted by SCATE. Each study employs a number of dependents measures that are designed to study pathology and measure efficacy. 1) Modulation of central glutamate by acamprosate A prevalent theory states that progressive emergence of a hyperglutamatergic state is key to the pathophysiology of alcoholism, and is associated both with emotional dysregulation (leading to craving and relapse), and neurotoxicity (leading to loss of grey matter and cognitive impairment). Acamprosate is a medication thought to target the hyperglutamatergic state. Here we used magnetic resonance spectroscopy (MRS) as a translational biomarker to obtain a measure of central glutamate using single-voxel 1H-MRS at 3T in the anterior cingulate cortex. Results showed a highly significant suppression of the glutamate to creatine ratio over time by acamprosate. This suggests that MRS offers an attractive biomarker for early human evaluation of candidate therapeutics that target the glutamatergic system. The results of this study have been published in Archives of General Psychiatry, 2010. 2) Alcohol craving induced by pharmacological stressors: yohimbine and mCPP Craving is a key element in the relapse process;therefore, a valid model of pharmacologically-induced alcohol craving might be useful to predict the efficacy of new pharmacotherapys for alcoholism, thereby accelerating drug development. To develop such a model, we tested two pharmacological challenges against a clinically established drug (acamprosate) for the treatment of alcoholism. In this protocol, we utilized a double-blind, placebo-controlled paradigm in which we administered: 1) an alpha 2-adrenergic antagonist (Yohimbine) which reliably induces reinstatement of alcohol seeking behavior in experimental animals, 2) a serotonergic compound (mCPP) which robustly increases alcohol craving in human alcoholics, and 3) placebo. Results showed cravings were significantly higher following both yohimbine and mCPP challenge compared with saline infusion. mCPP, but not yohimbine significantly increased anxiety ratings. Both challenges produced robust ACTH, cortisol and prolactin responses. Supporting the construct validity of the yohimbine response, we found a significant correlation between yohimbine-induced craving and the degree of alcoholism severity. Acamprosate administration did not influence craving. The results of this study have been published in Neuropsychopharmacology, 2011. 3) Effect of naltrexone on craving and ethanol-induced brain activity Findings from animal and human studies indicate that the rewarding properties of ethanol arise in part from a complex interaction between alcohol, endogenous opioids, and dopamine systems. Naltrexone (NTX), an opioid receptor antagonist, has been studied widely in both preclinical and clinical research for the treatment of alcoholism. Numerous clinical studies have shown that short-term use of NTX in alcohol-dependent patients effectively prevents relapse and reduces the level of craving. This protocol is the first study which involves administering IV alcohol to treatment-seeking alcohol dependent patients. Following detoxification, patients are randomized, using a double-blind design, to receive NTX or placebo throughout the course of their hospitalization. This study examines interactions between brain alcohol exposure and naltrexone treatment on processing of positive and negative emotional stimuli using fMRI. Patient recruitment for this study is complete, and data analysis is ongoing. 4) NK1R antagonism in alcoholism co-morbid with PTSD Alcoholism is the most common co-morbidity in men with PTSD and the second most common in women with this disorder. It is theorized that stress associated with PTSD (e.g., fear/anxiety, anger, hyper vigilance) promotes negatively reinforced use of alcohol to cope with negative affect. Therefore, we hypothesized that Substance P (SP)/NK1R signaling may be an attractive target for treatment of co-morbid alcoholism and PTSD. We asked whether NK1R blockade will suppress alcohol craving induced by stress or alcohol-associated stimuli, and whether it will improve PTSD symptoms in patients with co-morbid alcoholism and PTSD. This is an ongoing study, and results are not expected for another 18 months. 5) Corticotropin-releasing hormone receptor 1 (CRH1) antagonism and stress-induced craving in alcohol dependent women with high anxiety As alcoholism evolves, a shift occurs from positively to negatively reinforced alcohol use. Along the way, stress becomes a major trigger of relapse and excessive alcohol intake. Corticotrophin-releasing hormone (CRH) plays a major role in this state. We have negotiated a CRADA with GlaxoSmitKline, obtained an IND, and initiated a protocol that uses GSK561679 (CRH antagonist) as a translational tool in anxious female alcoholics. (Preclinical toxicology studies show that its use leads to a suppression of spermatogenesis, thus precluding its use in males.) The hypothesis is that GSK561679 will reduce alcohol craving in response to the combined challenges of the Trier Social Stress Task, alcohol-cue exposure, and guided imagery scripts. We will also examine whether GSK561679 will reduce spontaneous craving, reduce fMRI BOLD responses to negative affective stimuli within the ventral visual stream, medial temporal lobe and/or the anterior insula, and modulate blood markers of endocrine function in a manner indicative of anti-stress effects. Fifteen subjects have been enrolled, and 10 have completed. 6) CRH1 antagonism in anxious alcoholics This study uses another CRH1 antagonist, pexacerfont, obtained through a CRADA with Bristol Meyers Squibb. Pexacerfont is also an orally available, brain penetrant selective CRH1 antagonist. It has the advantage that safety has been established for the administration in both males and females. Because of the broader utility of pexacerfont in a therapeutic area where the majority of patients are male, we chose pexacerfont as the tool for a consortium of NIAAANIDA investigators who will use it in a cluster of related protocols. In the pexacerfontalcohol protocol, we will examine whether the CRH1 antagonist will reduce alcohol craving in response to the challenges as previously described for the GSK561679 CRH antagonist. We will also examine whether pexacerfont will reduce fMRI BOLD responses to a novel social stress challenge developed jointly with our NIDA collaborators. Six subjects have so far been enrolled, and 3 have completed. 7) Collaborative project with NIMH: Imaging Cannabinoid CB1 Receptors in Patients with Alcohol Dependence The brain endocannabinoid (EC) system involves endogenous cannabinoid agents (ECs) that act upon specific receptors (CB1 and CB2). ECs and CB1 receptors appear to modulate the brain reward system. During chronic alcohol exposure, EC levels in the brain are elevated and CB1 receptor levels are consequently reduced;this appears to be reversible following withdrawal. To what extent ECs and CB1 receptors are involved in the pathophysiology of alcohol dependence in humans is currently unknown. In this protocol, we utilize positron emission tomography to explore CB1 receptor abnormalities at various stages of alcohol withdrawal in humans. We are currently recruiting patients for this study. 8) Pilot study of deep brain stimulation (DBS) for the treatment of alcoholism Case reports of beneficial effects from DBS of the ventral striatum in alcoholism have been published, but no controlled data are available. In collaboration with NINDS and Medtronic, a DBS protocol that uses a controlled design has been developed, and is under review by the FDA.